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Alzheimer's disease (AD) is the most common cause of dementia and no cure is available at the moment. As the disease progresses, patients become increasingly dependent, needing constant supervision and care. Prevention or delay of AD onset is among the most urgent moral, social, economic and scientific imperatives in industrialized countries. A better understanding of the pathogenic mechanisms leading to the disease and the consequent identification of new pharmacological targets are now a need. One of the most prominent molecular events occurring in AD patients’ brains is the deposition of a peptide named amyloid-β (Aβ). Aβ derives from the concerted action of β-secretase, which mediates the amyloid precursor protein (APP) shedding at Aβ N-terminus, and γ-secretase, responsible for APP C-terminal stub cleavage. The production of Aβ can be prevented by the cleavage of ADAM10 on APP. In regard of AD pathogenesis, it is notable that neurons are the cell type affected in AD and that APP and the secretases are all integral transmembrane proteins, and so they are dynamically sorted in neurons. Therefore, neuronal sorting mechanisms responsible for APP and the secretases colocalization in the same membranous compartment play important roles in the regulation of Aβ production. In light of these considerations, this review provides an overview on the actual knowledge of the trafficking mechanisms involved in the regulation of APP and secretases localization, paying particular attention to the specific neuronal setting.

Synapse-asssociated protein-97 (SAP97) is responsible for the trafficking of both glutamate receptor subunits, GluR1 and NR2A, and α-secretase ADAM10 to the synaptic membrane. Here we evaluate the trafficking capability of SAP97 in Alzheimer disease (AD) patients' brain. We analyzed autoptic hippocampus and superior frontal gyrus, respectively as an affected and a less affected area, from 6 AD patients (Braak 4) and 6 healthy controls. In hippocampus, but not in superior frontal gyrus, of AD patients, ADAM10 and GluR1 synaptic membrane levels are altered while NR2A localization is not affected. Both immunoprecipitation and pull-down assays demonstrated that SAP97 failed to correctly couple to ADAM10 and GluR1, but not to NR2A. These findings not only indicate SAP97 as a point of convergence between amyloid cascade and synaptic failure in AD, but also allow a different interpretation of AD which can be now perceived as synaptic trafficking defect pathology.